The pathogenic mechanism of type 2 diabetes (T2D) is incompletely understood and effective treatments are limited. Our group has recently uncovered a potential role of the autophagy pathway in the pathogenesis of T2D. Autophagy is an essential lysosomal degradation pathway for energy balance and cell survival, and is the major mechanism that cells use to recycle nutrients and clear damaged organelles in response to stress. Both sedentary lifestyle and overly rich nutrition, the two causative factors of the global prevalence of T2D, impairs the autophagy activity; whereas fasting and physical exercise, two effective methods to prevent T2D, can potently induce autophagy. Thus, autophagy may mediate the beneficial effects of fasting and exercise against diabetes, and it is intriguing to investigate whether and how stimulation of autophagy may protect against T2D. Accordingly, we generated a novel mouse line that manifests constitutively active autophagy even without treatment of autophagy inducers, caused by a knockin point mutation in the essential autophagy gene Becn1. Interestingly, these autophagy-hyperactive mice are more glucose intolerant, but are more insulin sensitive, than mice with normal levels of autophagy in response to high-fat diet challenge. Together with other preliminary evidence, we propose a model in which insulin-producing ? cells and insulin-responsive cells may require different levels of autophagy for optimal metabolic function. We hypothesize that chronic autophagy activation degrades insulin granules and decreases insulin load in ? cells, but improves insulin sensitivity in insulin-responsive metabolic tissues. To test this hypothesis, we will focus on the function of two Beclin/Becn family members, Becn1 and Becn2, and propose the following 3 aims: Aim 1 is to determine the impact of Beclin-mediated hyperactivation of autophagy on insulin storage and secretion in ? cells; Aim 2 is to determine the role of Beclin-dependent autophagy activation in insulin sensitization in insulin-responsive tissues; and Aim 3 is to establish a strategy to increase insulin sensitivity in insulin-responsive tissues without affecting insulin storage in ? cells by transiently or periodically activating autophagy. Overall, using our autophagy-hyperactive and -deficient mouse models and novel autophagy-inducing compounds we identified from a library screen, we will elucidate how Beclin proteins regulate insulin production and responsiveness, understand the mechanisms by which autophagy activation prevents T2D, and develop new therapeutic reagents and approach against T2D.